Circadian and homeostatic contributions to physiology cognition and genome-wide expression in human and mouse variants of the PER3 VNTR polymorphism

PER3 VNTR 多态性的人类和小鼠变体的昼夜节律和稳态对生理认知和全基因组表达的贡献

• 批准号: BB/F022883/1
• 负责人: Derk-Jan Dijk
• 金额: $ 184.32万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF022883%2F1
• 关键词: Circadian; homeostatic; contributions; physiology; cognition

Our sleep-wake cycles are regulated by two clocks / the circadian clock, which has a stable period near 24 h, and a sleep homeostat, which keeps track of how long we have been asleep and awake. It is the interaction between these two clocks that determines whether, at any given time, we feel sleepy or not. Individual variation in these clocks and their interaction also determines whether we are a long or short sleeper, a morning or evening type and whether or not we are very sensitive to the effects of sleep loss on performance. The physiological and molecular mechanisms, as well as the genetic basis for these individual differences in sleep-wake regulation, are not very well known, but the study of 'clock' genes offers real potential for uncovering these mechanisms. PERIOD3, which is one of the clock genes, exists in one longer and one shorter form in humans. This variation is associated with whether you are a morning or evening type. We also showed that this difference has an influence on how much deep sleep we have and how we perform during a night without sleep. It does not affect the timing of the circadian clock. The data suggest that this polymorphism has an influence on the characteristics of our sleep-wake cycles primarily by affecting the sleep homeostat rather than the circadian clock. In the proposed research, we will test the hypothesis that the variation in PERIOD3 influences the sleep homeostat rather than the circadian clock, and also investigate the potential molecular mechanisms by which it affects the characteristics of the sleep and cognition. The research will be conducted in humans and mice. We will study humans carrying different combinations of the longer and the shorter version of the gene, and mice in which their native Period3 gene has been replaced with the two human variants. To characterise the impact of differences in PERIOD3 on either the circadian clock or the sleep homeostat, the sleep-wake cycle will be desynchronised from the circadian clock. This will be accomplished by forcing the sleep-wake cycle to a period much longer than 24 h. The circadian clock cannot keep up with such a long period. Under these circumstances we have separated the biological effects of the circadian clock and the sleep homeostat and we can now test the specific predictions that the PERIOD3 gene affects the homeostatic regulation of sleep and cognitive performance. We will do this by frequent measurements of sleep and performance and a large number of physiological variables. We will also collect blood samples from humans and tissue samples from mice. These samples will be used to assess the circadian variation in expression of >41,000 unique genes and alternative transcripts from human and mouse tissues as well as the circadian variation in the protein encoded by the PERIOD3 gene. The PERIOD3 protein rhythm and the gene expression rhythms will be compared between individuals carrying different variants of the gene. This may provide insights into the molecular mechanism by which the variation of the gene exerts its effects. Tissue samples from humans and mice will also be used to study the period of the circadian clock at the molecular level in cell cultures of these samples. These molecular periods will be compared the period of the clock as measured from the behaviour and hormonal rhythms in the whole organism in an attempt to discover whether variation in PERIOD3 affects this relationship. The proposed research will be conducted by a multidisciplinary team with expertise in sleep and circadian physiology, cognitive psychology, as well as molecular and systems biology. It will contribute to our understanding of the basic mechanisms underlying the daily regulation of sleep duration and timing, cognitive performance and its worsening following sleep loss. This basic knowledge may ultimately be applied to the development of treatments of the many and highly prevalent disorders of sleep-wake cycles.

我们的睡眠唤醒周期由两个时钟 /昼夜节律调节，该时钟稳定，接近24小时，睡眠体内稳态，可以跟踪我们已经睡着了多长时间。这两个时钟之间的相互作用决定了在任何给定时间是否感到困倦。这些时钟及其相互作用的个体变化也决定了我们是卧铺还是短的卧铺，早晨还是晚上类型，以及我们是否对睡眠损失对性能的影响非常敏感。生理和分子机制以及在睡眠效益调节中这些个体差异的遗传基础并不是很清楚，但是对“时钟”基因的研究为发现这些机制提供了真正的潜力。时钟基因之一的时期3以更长的形式存在于人类中。这种变化与您是早晨还是晚上类型有关。我们还表明，这种差异会影响我们有多深的睡眠以及在没有睡眠的情况下的表现。它不会影响昼夜节律的时间。数据表明，这种多态性主要是通过影响睡眠体内稳态而不是昼夜节律时钟对我们的睡眠效果周期的特征产生影响。在拟议的研究中，我们将检验以下假设：SECE3的变化会影响睡眠体内平衡而不是昼夜节律时钟，并研究它影响睡眠和认知特征的潜在分子机制。该研究将在人类和小鼠中进行。我们将研究携带较长和较短版本的不同组合的人类，并且其本地周期3基因已被两个人类变体取代的小鼠。为了表征周期3的差异对昼夜节律或睡眠体内平衡的影响，睡眠效果周期将与昼夜节律之间的同步。这将通过迫使睡眠效果周期到超过24小时的时间来实现。昼夜节律无法跟上这么长的时间。在这种情况下，我们将昼夜节律时钟和睡眠体内平衡的生物学作用分开，现在我们可以测试该时期3基因影响睡眠和认知性能的体内平衡调节的具体预测。我们将通过经常测量睡眠和表现以及大量生理变量来做到这一点。我们还将从小鼠的人类和组织样本中收集血液样本。这些样品将用于评估> 41,000个独特基因表达的昼夜节律变化，以及来自人类和小鼠组织的替代转录本，以及由SEECT3基因编码的蛋白质中的昼夜节律变化。将比较携带基因不同变异的个体之间的SEEC3蛋白节奏和基因表达节奏。这可以提供有关基因变异产生其作用的分子机制的见解。来自人类和小鼠的组织样品也将用于研究这些样品细胞培养的分子水平的昼夜节律时期。这些分子周期将被比较，从整个生物体中的行为和激素节奏中测量的时钟周期，以发现时期3中的变化是否影响这种关系。拟议的研究将由一个多学科团队进行，该团队在睡眠和生理学，认知心理学以及分子和系统生物学方面具有专业知识。这将有助于我们理解睡眠持续时间和时间安排，认知表现以及睡眠损失后其恶化的基本机制。这种基本知识最终可以应用于许多睡眠效果周期疾病的治疗方法的发展。

项目成果

Neuroimaging, cognition, light and circadian rhythms.

• DOI: 10.3389/fnsys.2014.00126
• 发表时间: 2014
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Gaggioni G;Maquet P;Schmidt C;Dijk DJ;Vandewalle G
• 通讯作者: Vandewalle G

Phenotyping of PER3 variants reveals widespread effects on circadian preference, sleep regulation, and health

• DOI: 10.1016/j.smrv.2017.10.008
• 发表时间: 2018-08-01
• 期刊: SLEEP MEDICINE REVIEWS
• 影响因子: 10.5
• 作者: Archer, Simon N.;Schmidt, Christina;Dijk, Derk-Jan
• 通讯作者: Dijk, Derk-Jan

A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.

• DOI: 10.1096/fj.13-240135
• 发表时间: 2014-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Hasan S;van der Veen DR;Winsky-Sommerer R;Hogben A;Laing EE;Koentgen F;Dijk DJ;Archer SN
• 通讯作者: Archer SN

Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin.

人类昼夜节律的评估：实时成纤维细胞报告成像与血浆褪黑激素的比较。

• DOI: 10.1096/fj.11-201699
• 发表时间: 2012-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Hasan S;Santhi N;Lazar AS;Slak A;Lo J;von Schantz M;Archer SN;Johnston JD;Dijk DJ
• 通讯作者: Dijk DJ

Circadian and Homeostatic Regulation of Human Sleep and Cognitive Performance and Its Modulation by PERIOD3.

• DOI: 10.1016/j.jsmc.2009.02.001
• 发表时间: 2009-06
• 期刊: Sleep medicine clinics
• 影响因子: 2.8
• 作者: Dijk DJ;Archer SN
• 通讯作者: Archer SN